IRIC - Institute for Research in Immunology and Cancer

Published on February 20, 2017

SUMOylation of the proteasome on its outer surface (left) allows its association with PML nuclear bodies by promoting its connection with the SUMO interaction domain (SIM) of the PML protein, whereas this binding is compromised when the domain SIM is missing (right).

The team of Pierre Thibault, Principal Investigator at the Institute for Research in Immunology and Cancer (IRIC) and professor in the Department of Chemistry of the Université of Montréal, in collaboration with colleagues from the University Paris-Descartes recently published in the journal Nature Communications a new proteomics approach for the global-scale analysis of protein SUMOylation with unprecedented sensitivity and depth. SUMOylation, an important type of protein modification, regulates many cellular processes such as cell division, intracellular trafficking, protein degradation and senescence. An imbalance of this modification can result in cell proliferation and the development of tumors.

Within cells, the activity of many proteins is governed by different reversible chemical modifications. Ubiquitylation and SUMOylation are two such modifications that involve the transfer of small proteins, respectively called Ubiquitin (Ub) and SUMO (Small Ubiquitin-like Modifier), to specific sites on the targeted proteins. In particular, Ub often acts as a tag that marks proteins for degradation by the proteasome, a normal and essential process. Indeed, in the cell, there is a continual turnover of proteins, which implies a permanent process of synthesis and degradation. This dynamic between synthesis and degradation ensures the quality control of proteins and allows the cell to adapt quickly to changes in its environment.

The new approach described recently allows a deeper analysis of the regulation of proteins modified by SUMOylation. The researchers found that many proteins are modified by both SUMOylation and ubiquitylation and that there is a functional crosstalk between these changes. In addition, this work revealed a new mechanism by which the proteasome undergoes strong SUMOylation during a cellular stress and this modification is necessary for its interaction with the PML nuclear bodies, an organelle associated with the degradation of some nuclear proteins. This perturbation of the interaction between the proteasome and PML nuclear bodies can lead to the proliferation of leukemic cells in acute promyelocytic leukemia.

This recent study opens new avenues for the identification of protein substrates, their specific modification sites, the interaction between SUMOylation and ubiquitylation, and their regulation in different diseases.

The new proteomics approach developed by the Pierre Thibault’s team to study proteins modified by SUMOylation and Ubiquitylation involves the purification of cellular proteins, their digestion in small peptides and the immunoprecipitation of the SUMOylated and Ubiquitylated peptides. These peptides are then separated by chromatography and identified by mass spectrometry.

Cited study

Frédéric Lamoliatte, Francis McManus, Ghizlane Maarifi, Mounira K. Chelbi-Alix, Pierre Thibault, Uncovering the SUMOylation and ubiquitylation crosstalk in human cells using sequential peptide immunopurification, Nature Communications 2017, 8:14109.